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Patients with stage IIIA NSCLC and N2 (mediastinal) disease have a poor outcome, with long term overall survival consistently reported to be approximately 20%

Definitive concurrent chemoradiation is the standard of care in good performance status patients

Surgical resection has been demonstrated to possibly improve on these results, but with the cost of increased morbidity and mortality, so there is debate as to whether or not surgery adds any benefit in these patients

All patients were randomized initially, then underwent identical induction therapy consisting of thoracic radiation to 45 Gy with concurrent chemotherapy: cisplatin 50 mg/m2 days 1, 8, 29, and 36 and etoposide 50 mg/m2 days 1-5 and days 29-33

Those randomized to the surgical arm underwent resection if there was no progressive disease

Those randomized to chemoradiation continued to 61 Gy with 2 additional doses of chemotherapy, without treatment break

Median follow up was 81 months, with all patients followed at least 2.5 years

Results

88% of patients randomized to surgery were eligible and 81% underwent resection, with complete responses to induction of 71%

92% of patients randomized to CT/RT were eligible for definitive CT/RT and 80% received full dose of radiation

Grade 3/4 toxicities from CT/RT were fairly similar, with the exception of esophagitis rates of 44% in the definitive CT/RT arm vs. 20% in the surgical arm

Treatment related death rate in the surgical arm was 7.9%, with 14/15 of these deaths coming from patients who underwent pneumonectomy (26% death rate in patients requiring pneumonectomy). The majority of these were right sided cases, and the major cause was ARDS

Treatment related deaths in the CT/RT arm was 2.1%

Patients had an increased PFS in the surgical arm (5 year PFS of 22% vs. 11% and Median PFS of 12.8 months vs. 10.5 months)

In a matched control analysis, investigating pneumonectomy patients with matched CT/RT patients, pneumonectomy patients had a poorer survival, with median survival times of 19 months compared to 29 months

Patterns of failure in the surgical arm was 10% local failure only and 37% distant metastases vs. 22% local failure and 42% distant metastases in the CT/RT arm

Multivariate analysis showed weight loss, male gender, and >1 nodal station involved were predictive for worse survival, but treatment arm was not

Author's Conclusions

Longer follow up confirms improved PFS in the surgical arm, but with no improvement in OS

There was a trend for increased OS in the surgical arm, with 7% improvement at 5 years

N0 status at surgery predicts for better survival

Surgical resection after induction CT/RT should be considered in patients with N2 disease if pneumonectomy is not required

Clinical/Scientific Implications

The treatment of stage IIIA NSCLS is controversial. Standard of care is definitive chemoradiation, though many have advocated surgery in attempts to improve the results. This study shows an increased PFS but without an effect on OS. It is easy to see that there will never be an OS benefit in this study because of the number of postoperative deaths in the surgical arm. However, all but one death occurred in patients who had undergone pneumonectomy, with only 1 death out of 98 lobectomy patients. This indicates that in carefully selected patients, surgery following induction chemoradiation may improve the results. However, the key is the selection, and it appears that patients requiring pneumonectomy would be poorly served by attempts at surgical resection. Optimal treatment for this heterogeneous disease will likely continue to be debated.